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Geometry of Brain’s Outer Surface Correlates With Genetic Heritage

Geometry of Brain’s Outer Surface Correlates With Genetic Heritage | Amazing Science | Scoop.it

Researchers at the University of California, San Diego and the School of Medicine have found that the three-dimensional shape of the cerebral cortex – the wrinkled outer layer of the brain controlling many functions of thinking and sensation – strongly correlates with ancestral background.


The study, published online July 9 in Current Biology, opens the door to more precise studies of brain anatomy going forward and could eventually lead to more personalized medicine approaches for diagnosing and treating brain diseases. 


“If we can account for a large percentage of brain structure based on an individual’s genes, we’re in a better position to detect smaller variations in the brain that might be important in understanding disease or developmental issues,” said the study’s senior author Anders Dale, PhD, professor of radiology, neurosciences, psychiatry and cognitive science, and director of the Center for Translational Imaging and Precision Medicine at UC San Diego.


In their study, the researchers found they could predict with “a relatively high degree of accuracy an individual’s genetic ancestry based on the geometry of their cerebral cortex.” They found no relationship between brain shape and functional or cognitive abilities, Dale said, but rather a trove of information about how minute differences in brain geometry could be correlated with genetic lineage. 


“The geometry of the brain’s cortical surface contains rich information about ancestry,” said the study’s first author, Chun Chieh Fan, MD, a graduate student in cognitive science. “Even in the modern contemporary U.S. population, with its melting pot of different cultures, it was still possible to correlate brain cortex structure to ancestral background.”


Four continental populations were used as ancestral references: European, West African, East Asian and Native American. The metrics for summarizing genetic ancestry in each ancestral component were standardized as proportions ranging from 0 to 100 percent. 


“We looked to see how well we could predict how much genetic ancestry they had from Africa, Europe and so forth,” said study co-author Terry Jernigan, PhD, professor of cognitive science, psychiatry and radiology, adding that cortex differences between various lineages were focused in certain areas. “There were various systematic differences, particularly in the folding and gyrification patterns of the cortex,” said Jernigan, also director of the university’s Center for Human Development. “Those patterns were quite strongly reflective of genetic ancestry.” 


The researchers reported that the cortical patterns accounted for 47 to 66 percent of the variation among individuals in their genetic ancestry, depending on the ancestral lineage.

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Sequencing Uncovers New Monogenic Form of Obesity

Sequencing Uncovers New Monogenic Form of Obesity | Amazing Science | Scoop.it

A team from the UK, the Netherlands, and Ireland has identified a form of inherited obesity and type 2 diabetes that appears to stem from a mutation in a single enzyme-coding gene. As they reported online in PLOS One, the researchers did exome sequencing on members of a consanguineous family affected by a condition characterized by extreme obesity, type 2 diabetes, intellectual disability, and other features. Their search led to truncating mutations affecting both copies of a gene that codes for a peptide-processing enzyme called carboxypeptidase E.


That enzyme normally plays a role in regulating hormone and neuropeptide peptides, the team explained. And past mouse studies suggest that mutations that alter the enzyme's ability to regulate such peptides can throw off appetite control, normal glucose metabolism, and other physiological processes.


"There are now an increasing number of single-gene causes of obesity and diabetes known," corresponding author Alexandra Blakemore, a diabetes, endocrinology, and metabolism researcher at the Imperial College of Medicine, said in a statement.


"We don't know how many more have yet to be discovered, or what proportion of the severely obese people in our population have these diseases — it is not possible to tell just by looking," Blakemore added, explaining that such inherited conditions can affect individuals' bodies and their ability to appropriately respond to hunger and fullness signals.


In an effort to track down new genes that contribute to inherited, single-gene forms of obesity, the researchers performed exome sequencing on members of a Sudanese family found through a genetic obesity clinic at a UK hospital.


Using the Agilent SureSelectXT Human All Exon V4+UTR kit, the team isolated protein-coding DNA from an affected family member — a morbidly obese 21-year-old woman with childhood-onset obesity, type 2 diabetes, intellectual disability, and reproductive problems — along with her mother and sister. After sequencing these exomes with the Illumina HiSeq 2500, the researchers scrutinized the sequences for single nucleotide changes, small insertions and deletions, and copy number variants.


The search ultimately led to a truncating frameshift mutation in the first exon of the CPE gene. With the help of Sanger sequencing, the team determined that the affected woman carried two copies of this mutation, while her mother, sister, and two brothers had one copy of the altered CPE gene. Similarly, when researchers used real-time PCR to track expression of the gene in blood samples from family members and female controls, they did not detect CPE transcripts in blood samples from the affected women. A sister with one copy of the mutation had lower-than-usual CPE expression compared to six control individuals.


The study's authors argued that the newly detected mutation, together with those in other genes involved in monogenic forms of obesity, should provide opportunities to find the basis of disease in ever more individuals with inherited obesity.


"Diagnosis is very valuable to the patient. It helps to set realistic expectations, and can help them get the best possible treatment," Blakemore noted, explaining that such diagnoses also make it possible to provide genetic counseling and advice to other members of affected families. 

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New color blindness gene identified: ATF6

New color blindness gene identified: ATF6 | Amazing Science | Scoop.it

A rare eye disorder marked by color blindness, light sensitivity, and other vision problems can result from a newly discovered gene mutation identified by an international research team, including scientists from Columbia University Medical Center (CUMC). The findings, which were published today in the online edition of Nature Genetics, could lead to new, targeted treatments for this form of color blindness.


The researchers found that mutations to a gene called ATF6, a key regulator of the unfolded protein response, can lead to achromatopsia, a hereditary visual disorder characterized by color blindness, decreased vision, light sensitivity, and uncontrolled eye movement in children. The unfolded protein response is a mechanism cells use to prevent the dangerous accumulation of unfolded or mis-folded proteins.


Based on mouse studies, the researchers suspect that the cone cells of people with achromatopsia are not permanently damaged and could be revived by enhancing the pathway that regulates the unfolded protein response. "Several drugs that activate this pathway have already been approved by the FDA for other conditions and could potentially benefit patients with achromatopsia," said one of the study leaders, Stephen Tsang, MD, PhD, who is the Laszlo Z. Bito Associate Professor of Ophthalmology, and is affiliated with the Institute of Human Nutrition, at CUMC.


"Dr. Tsang's innovative research continues to unfold the genetic basis for a variety of ocular diseases. This finding is an example of the finest clinically based science that will ultimately allow us to overcome preventable vision loss," said George A. Cioffi, MD, Edward S. Harness Chairman and Ophthalmologist-in-Chief at NewYork-Presbyterian Hospital/Columbia University Medical Center.


"Five genes had previously been linked to achromatopsia; however, they accounted for only about half of all cases," said Dr. Tsang. "Using next-generation gene sequencing on a small group of patients, we found that mutations in a sixth gene -- ATF6 -- can independently lead to the disease."

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Mice embryos grow a bigger brain with human DNA

Mice embryos grow a bigger brain with human DNA | Amazing Science | Scoop.it

The size of the human brain expanded dramatically during the course of evolution, imparting us with unique capabilities to use abstract language and do complex math. But how did the human brain get larger than that of our closest living relative, the chimpanzee, if almost all of our genes are the same?


Duke scientists have shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and then visualize their respective contributions to early brain development by using mouse embryos. The team found that humans are equipped with tiny differences in a particular regulator of gene activity, dubbed HARE5, that when introduced into a mouse embryo, led to a 12% bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.


The findings, appearing online Feb. 19, 2015, in Current Biology, may lend insight into not only what makes the human brain special but also why people get some diseases, such as autism and Alzheimer's disease, whereas chimpanzees don't.


"I think we've just scratched the surface, in terms of what we can gain from this sort of study," said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School. "There are some other really compelling candidates that we found that may also lead us to a better understanding of the uniqueness of the human brain."


Every genome contains many thousands of short bits of DNA called 'enhancers,' whose role is to control the activity of genes. Some of these are unique to humans. Some are active in specific tissues. But none of the human-specific enhancers previously had been shown to influence brain anatomy directly.


In the new study, researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritized enhancers that differed markedly between the two species. The group's initial screen turned up 106 candidates, six of them near genes that are believed to be involved in brain development. The group named these 'human-accelerated regulatory enhancers,' HARE1 through HARE6.


The strongest candidate was HARE5 for its chromosomal location near a gene called Frizzled 8, which is part of a well-known molecular pathway implicated in brain development and disease. The group decided to focus on HARE5 and then showed that it was likely to be an enhancer for Frizzled8 because the two DNA sequences made physical contact in brain tissue.


The human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters in their genetic code. Yet, in mouse embryos the researchers found that the human enhancer was active earlier in development and more active in general than the chimpanzee enhancer.


"What's really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," Silver said.

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Birdsong and human speech turn out to be controlled by the same genes

Birdsong and human speech turn out to be controlled by the same genes | Amazing Science | Scoop.it

New research on the bird genome has revealed that the same genes that give humans the ability to speak give birds the ability to sing. Because of this similarity, researchers will be able to use birds as lab subjects to better understand how speech evolved.


Duke University neuroscientist Erich Jarvis led a study on birdsong and speech published recently in Science. But he also co-led the greater effort that made it possible -- the mapping of 48 bird genomes. This unprecedented look at the genetic make-up of all kinds of birds allowed researchers to answer questions on everything from crocodile evolution to bird teeth. But Jarvis was always driven by avian musicality.


"I've always been interested in how the brain controls complex behaviors, and I became most interested in speech," Jarvis said. But it's hard to study speech in humans -- you can't keep someone in a lab for their entire life or perform invasive experiments on them. Non-human primates are usually the best choice for study, but other primates don't learn to mimic vocal sounds the way humans do. But birds fit the bill.


Several papers on vocal learning in birds were released as part of the genome study, but Jarvis's favorite is one that describes how a computational biologist in his lab crunched all of the data sets together to find genes that lined up between birds. They found a consistent set of around 50 genes that seem to correlate with vocal learning: If a gene was more active in humans, it was also more active in birds who could learn songs (and the same held true if the gene was less active). These changes weren't seen in birds who don't learn songs or in non-speaking primates.

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Genetic factors behind surviving or dying from Ebola shown in mouse study

Genetic factors behind surviving or dying from Ebola shown in mouse study | Amazing Science | Scoop.it

A newly developed mouse model suggests that genetic factors are behind the mild-to-deadly range of responses to the Ebola virus. The frequency of different manifestations of the disease across the lines of these mice are similar in variety and proportion to the spectrum of clinical disease observed in the 2014 West African outbreak. The new mouse model might be useful in testing candidate therapeutics and vaccines for Ebola, and in finding genetic markers for susceptibility and resistance to the disease.


Research on Ebola prevention and treatment has been hindered by the lack of a mouse model that replicates the main characteristics of human Ebola hemorrhagic fever. The researchers had originally obtained this genetically diverse group of inbred laboratory mice to study locations on mouse genomes associated with influenza severity.


The research was conducted in a highly secure, state-of-the-art biocontainment safety level 4 laboratory in Hamilton, Mont. The scientists examined mice that they infected with a mouse form of the same species of Ebola virus causing the 2014 West Africa outbreak. The study was done in full compliance with federal, state, and local safety and biosecurity regulations. This type of virus has been used several times before in research studies. Nothing was done to change the virus.


Interestingly, conventional laboratory mice previously infected with this virus died, but did not develop symptoms of Ebola hemorrhagic fever.


In the present study, all the mice lost weight in the first few days after infection. Nineteen percent of the mice were unfazed. They not only survived, but also fully regained their lost weight within two weeks. They had no gross pathological evidence of disease. Their livers looked normal. Eleven percent were partially resistant and less than half of these died. Seventy percent of the mice had a greater than 50 percent mortality. Nineteen percent of this last group had liver inflammation without classic symptoms of Ebola, and thirty-four percent had blood that took too long to clot, a hallmark of fatal Ebola hemorrhagic fever in humans. Those mice also had internal bleeding, swollen spleens and changes in liver color and texture.


The scientists correlated disease outcomes and variations in mortality rates to specific genetic lines of mice.

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Genes don't just influence your IQ—they determine how well you do in school

Genes don't just influence your IQ—they determine how well you do in school | Amazing Science | Scoop.it

Twin study shows that many different inherited traits shape a person's grades and test scores.


If you sailed through school with high grades and perfect test scores, you probably did it with traits beyond sheer smarts. A new study of more than 6000 pairs of twins finds that academic achievement is influenced by genes affecting motivation, personality, confidence, and dozens of other traits, in addition to those that shape intelligence. The results may lead to new ways to improve childhood education.


“I think this is going to end up being a really classic paper in the literature,” says psychologist Lee Thompson of Case Western Reserve University in Cleveland, Ohio, who has studied the genetics of cognitive skills and who was not involved in the work. “It’s a really firm foundation from which we can build on.”


Researchers have previously shown that a person’s IQ is highly influenced by genetic factors, and have even identified certain genes that play a role. They’ve also shown that performance in school has genetic factors. But it’s been unclear whether the same genes that influence IQ also influence grades and test scores.


In the new study, researchers at King’s College London turned to a cohort of more than 11,000 pairs of both identical and nonidentical twins born in the United Kingdom between 1994 and 1996. Rather than focus solely on IQ, as many previous studies had, the scientists analyzed 83 different traits, which had been reported on questionnaires that the twins, at age 16, and their parents filled out. The traits ranged from measures of health and overall happiness to ratings of how much each teen liked school and how hard they worked. Then, the researchers collected data on how well each individual scored on the General Certificate of Secondary Education (GCSE) exam, an exam that all students in the United Kingdom must take and which is used for admission to advanced classes or colleges.


The team found nine general groups of traits that were all highly hereditary—the identical twins were more likely to share the traits than nonidentical twins—and also correlated with performance on the GCSE. Not only were traits other than intelligence correlated with GCSE scores, but these other traits also explained more than half of the total genetic basis for the test scores.

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Case of a missing gene may help future Alzheimer's treatment

Case of a missing gene may help future Alzheimer's treatment | Amazing Science | Scoop.it
Research suggests that reducing or neutralizing one variety of the APOE gene would not harm the brain, while making Alzheimer’s less likely.


The 40-year-old man showed up in Dr. Mary Malloy’s clinic with sadly disfiguring symptoms. His hands, elbows, ears and feet were blemished with protruding pustules and tuber-like welts, some so painful it was hard for him to walk. He suffered from a rare genetic condition called dysbetalipoproteinemia, which caused his cholesterol levels to soar so high that pools of fatty tissue seemed to bubble up under his skin.


But there was something else about this patient. He was missing a gene that, when present in one form, greatly increases the risk of developing Alzheimer’s disease. Dr. Malloy, who co-directs the Adult Lipid Clinic at the University of California, San Francisco, and her colleagues saw an opportunity to answer an important neurological riddle: Does the absence of the gene — named apolipoprotein E, or APOE, after the protein it encodes — hurt the brain?


If a person with this rare condition were found to be functioning normally, that would suggest support for a new direction in Alzheimer’s treatment. It would mean that efforts — already being explored by dementia experts — to prevent Alzheimer’s by reducing, eliminating or neutralizing the effects of the most dangerous version of APOE might succeed without causing other problems in the brain.


The researchers, who reported their findings on Monday in the journal JAMA Neurology, discovered exactly that. They ran a battery of tests, including cognitive assessments, brain imaging and cerebrospinal fluid analyses. The man’s levels of beta-amyloid and tau proteins, which are markers of Alzheimer’s, gave no indication of neurological disease. His brain size was unaffected, and the white matter was healthy. His thinking and memory skills were generally normal.


“This particular case tells us you can actually live without any APOE in the brain,” said Dr. Joachim Herz, a neuroscientist and molecular geneticist at University of Texas Southwestern Medical Center, who was not involved in the research. “So if they were to develop anti-APOE therapies for Alzheimer’s, we would not have to worry about serious neurological side effects.”

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Who's your daddy? Researchers program computer to find out

Who's your daddy? Researchers program computer to find out | Amazing Science | Scoop.it
A University of Central Florida research team has developed a facial recognition tool that promises to be useful in rapidly matching pictures of children with their biological parents and in potentially identifying photos of missing children as they age.


The work verifies that a computer is capable of matching pictures of parents and their children. The study will be presented at the nation's premier event for the science of computer vision - the IEEE Computer Vision and Pattern Recognition conference in Columbus, Ohio, which begins Monday, June 23. Graduate Student Afshin Dehfghan and a team from UCF's Center for Research in Computer Vision started the project with more than 10,000 online images of celebrities, politicians and their children.


"We wanted to see whether a machine could answer questions, such as 'Do children resemble their parents?' 'Do children resemble one parent more than another?' and 'What parts of the face are more genetically inspired?'" he said.


Anthropologists have typically studied these questions. However Dehghan and his team are advancing a new wave of computational science that uses the power of a mechanical "mind" to evaluate data completely objectively – without the clutter of subjective human emotions and biases. The tool could be useful to law enforcement and families in locating missing children.


"As this tool is developed I could see it being used to identify long-time missing children as they mature," said Ross Wolf, associate professor of criminal justice at UCF.


Wolf said that facial recognition technology is already heavily used by law enforcement, but that it has not been developed to the point where it can identify the same characteristics in photos over time, something this technology could have the capability to do. Dehghan said he is planning to expand on the work in that area by studying how factors such as age and ethnicity affect the resemblance of facial features.

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Single nucleotide mutation in c-KIT ligand gene is responsible for blond hair trait

Single nucleotide mutation in c-KIT ligand gene is responsible for blond hair trait | Amazing Science | Scoop.it
HHMI researchers find that a single-letter change in the genetic code is enough to generate blond hair in humans.


Genomic surveys by other groups had revealed that the gene – Kit ligand – is indeed evolutionarily significant among humans. “The very same gene that we found controlling skin color in fish showed one of the strongest signatures of selection in different human populations around the world,” Kingsley says. His team went on to show that in humans, different versions of Kit ligand were associated with differences in skin color.


Furthermore, in both fish and humans, the genetic changes associated with pigmentation differences were distant from the DNA that encodes the Kit ligand protein, in regions of the genome where regulatory elements lie. “It looked like regulatory mutations in both fish and humans were changing pigment,” Kingsley says.


Kingsley's subsequent stickleback studies have shown that when new traits evolve in different fish populations, changes in regulatory DNA are responsible about 85 percent of the time. Genome-wide association studies have linked many human traits to changes in regulatory DNA, as well. Tracking down specific regulatory elements in the vast expanse of the genome can be challenging, however.


“We have to be kind of choosy about which regulatory elements we decide to zoom in on,” Kingsley says. “We thought human hair color was at least as interesting as stickleback skin color.” So his team focused its efforts on a human pigmentation trait that has long attracted attention in history, art, and popular culture.


Kit ligand encodes a protein that aids the development of pigment-producing cells, so it made sense that changing its activity could affect hair or skin color. But the Kit ligand protein also plays a host of other roles throughout the body, influencing the behavior of blood stem cells, sperm or egg precursors, and neurons in the intestine. Kingsley wanted to know how alterations to the DNA surrounding this essential gene could drive changes in coloration without comprising Kit ligand's other functions.


Catherine Guenther, an HHMI research specialist in Kingsley's lab, began experiments to search for regulatory switches that might specifically control hair color. She snipped out segments of human DNA from the region implicated in previous blond genetic association studies, and linked each piece to a reporter gene that produces a telltale blue color when it is switched on. When she introduced these into mice, she found that one piece of DNA switched on gene activity only in developing hair follicles.


“When we found the hair follicle switch, we could then ask what's different between blonds and brunettes in northern Europe,” Kingsley said. Examining the DNA in that regulatory segment, they found a single letter of genetic code that differed between individuals with different hair colors.


Their next step was to test each version's effect on the activity of the Kit ligand gene. Their preliminary experiments, conducted in cultured cells, indicated that placing the gene under the control of the “blond” switch reduced its activity by about 20 percent, as compared to the "brunette" version of the switch. The change seemed slight, but Kingsley and Guenther suspected they had identified the critical point in the DNA sequence.


The scientists next engineered mice with a Kit ligand gene placed under the control of the brunette or the blond hair enhancer. Using technology developed by Liqun Luo, who is also an HHMI investigator at Stanford, they were able to ensure that each gene was inserted in precisely the same way, so that a pair of mice differed only by the single letter in the hair follicle switch—one carrying the ancestral version, the other carrying the blond version.


“Sure enough, when you look at them, that one base pair is enough to lighten the hair color of the animals, even though it is only a 20 percent difference in gene expression,” Kingsley says. “This is a good example of how fine-tuned regulatory differences may be to produce different traits. The genetic mechanism that controls blond hair doesn't alter the biology of any other part of the body. It's a good example of a trait that's skin deep—and only skin deep.”

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Germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with a 31% risk

Germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with a 31% risk | Amazing Science | Scoop.it

Two studies found that germline EGFR T790M mutation results in a rare and unique lung cancer hereditary syndrome associated with an estimated 31% risk for the disease in never-smokers. Lead author Adi Gazdar, MD, of the Department of Pathology, UT Southwestern Medical Center, Dallas, TX, and colleagues studied a family with germline EGFR T790M mutations over five generations (14 individuals) and combined their observations with data obtained from a literature search (15 individuals). They found that the mutation occurred in approximately 1% of NSCLCs and in less than one in 7,500 subjects without lung cancer.


Female never-smokers were overrepresented in the family cohort. Among 13 patients for whom gender and smoking status were known, nine were female never-smokers, two were male never-smokers, and two were ever-smokers (one male and one female).


“The risk of lung cancer development in never-smoking carriers is greater than the risk of heavy smokers with or without the mutation,” says Dr. Gazdar, who is an IASLC member. “Unaffected carriers with this mutation are at increased risk for the development of lung cancer irrespective of their smoking status and should be followed by increased surveillance, including low-dose computed tomography,” he adds.


The cancers associated with germline EGFR T790M mutations share several similar features with lung cancers containing sporadic EGFR mutations, such as a predominance for adenocarcinoma histology, female gender, and never-smoking status. However, a difference with lung cancers having sporadic EGFR mutations is a predominance for white ethnicity (compared with East Asian). 


“Germline EGFR T790M mutations are present in approximately 50% of all patients with baseline EGFR T790M identified in their tumor specimens before treatment,” says Dr. Yu, also an IASLC member. “In our practice, we recommend that all patients with baseline  EGFR T790M identified in their lung tumor tissue be referred to clinical genetics to discuss EGFR T790M germline testing. Carriers of this mutation need to be prospectively studied to better understand the clinical implications of this germline mutation.


The presence of a germline EGFR T790M mutation also predicts for resistance to standard tyrosine kinase inhibitors (TKIs), which adds complexity to treatment. Until newer third- and fourth-generation TKIs designed to overcome T790M-mediated resistance become available, standard chemotherapy may be the preferred first-line therapy option in the absence of another known or suspected molecular target.

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Why hospitals will soon sequence the genes of every single patient

Why hospitals will soon sequence the genes of every single patient | Amazing Science | Scoop.it

We are now on the verge of a health data breakthrough, in which computers will be able to do similar diagnostic tasks, by analyzing massive amounts of data, including genome sequences, risk factors, medical histories, drug interactions, and more.


Looking at this trend last year, venture capitalist Vinod Khosla made the bold claim that technology will replace 80 percent of companies eventually. The reality is probably more nuanced: Far from threatening to put doctors out of jobs, the falling prices of data analysis and genome sequencing are enabling them with tools they could only dream of even a few years ago.


At the Mount Sinai Hospital in New York, Joel Dudley, Ph.D. uses Ayasdi’s products to discover how patients with certain genes are more likely to develop some diseases (diabetes, cardiovascular conditions…) as well as how genes influence the performance of a treatment, or may reveal risks of later relapses that can be prepared for.


Already 11,000 patients at Mount Sinai have had their genome sequenced, a pool large enough for meaningful analysis, although Ayasdi tells us “those are still early days for the industry. There are no plans to act on that data directly with individual patients just yet.”


Right now the Mount Sinai community is working at organizing itself to make the useful information available to the frontline staff. And another 30,000 patients may soon sign the consent form and opt in to participate in this new way to explore which care is best for them.


The exploration of big data by the enterprise is becoming less of a competitive edge and turning into more of a must-have. Similarly, hospitals may have to adopt genetic analysis as a rule of thumb sooner rather than later.  Mount Sinai is unusual today in pioneering regular genetic screenings, but it soon may become commonplace.

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BGI to Sequence 2,200 Geniuses in Search for the "Genome Of The Genius"

BGI to Sequence 2,200 Geniuses in Search for the "Genome Of The Genius" | Amazing Science | Scoop.it
In the world of genomics, Chinese biotech giant BGI is big and getting bigger. The firm agreed to purchase Bay Area juggernaut Complete Genomics for a bargain basement $117 million in 2012.


BGI owns 156 DNA sequencers and produces 10% to 20% of the world’s genetic information. Now the firm is putting their DNA sequencing might behind an investigation into the genetics of genius.


Suitably, one of BGI’s homegrown savants, 20-year-old Zhao Bowen, will head up the study. According to his bio, Zhao dropped out of high school to join BGI “after a startlingly productive internship contributing to BGI’s cucumber sequencing project.” His smart gene study promises to be a bit more challenging.


According to the Wall Street Journal, 1,600 of the study’s 2,200 genomes were provided by Dr. Robert Plomin of King’s College, London. Plomin collected the DNA of individuals with IQs over 160 (average IQ is said to be around 100) who had previously participated in a program called the Study of Mathematically Precocious Youth. BGI signed up another 500 on their website. (The WSJ doesn’t account for the remaining 100.)


Zhao’s team is already busy sequencing the genomes and optimistically says they’ll be done in three months. The team will compare their genius genomes to a random selection of the population to see if they can isolate differences between the two.


Will they find anything useful? The WSJ compares the study to the genetics of height which depends on “1,000 genetic variations that partly explain why some people are taller than others.” It took 10,000 genomes for scientists to see results. If the genetic determinants of height are subtle and complicated, intelligence must be out of the ballpark, down at the pub, mumbling into a pint of ale.


BGI very clearly gets all this stuff. They know it’s a difficult and controversial topic. Sections of their FAQ read like a financial services disclaimer. “We do not claim that our study design is capable of identifying all g-associated alleles given enough participants, let alone all loci linked with other components of intelligence; or that g is a perfect measurement of intelligence, brain health, etc. We simply wish to start the process of discovery, and believe that this is a good place to begin.”


And maybe that’s enough for now. It’ll be fascinating, and probably controversial, when the team announces their findings. After all, if someone thinks they’ve found the genes behind intelligence—what then will they do with that information?

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Picture This? Some Just Can’t: Congenital aphantasia

Picture This? Some Just Can’t: Congenital aphantasia | Amazing Science | Scoop.it
Aphantasia, the inability to summon up mental images, is a little-known condition on the verge of wider study.


Certain people, researchers have discovered, can’t summon up mental images — it’s as if their mind’s eye is blind. In June 2015, in the journal Cortex, the condition received a name: aphantasia, based on the Greek word phantasia, which Aristotle used to describe the power that presents visual imagery to our minds.


In 2005, a 65-year-old retired building inspector paid a visit to the neurologist Adam Zeman at the University of Exeter Medical School. After a minor surgical procedure, the man — whom Dr. Zeman and his colleagues refer to as MX — suddenly realized he could no longer conjure images in his mind.


Dr. Zeman couldn’t find any description of such a condition in medical literature. But he found MX’s case intriguing. For decades, scientists had debated how the mind’s eye works, and how much we rely on it to store memories and to make plans for the future.


MX agreed to a series of examinations. He proved to have a good memory for a man of his age, and he performed well on problem-solving tests. His only unusual mental feature was an inability to see mental images.


Dr. Zeman and his colleagues then scanned MX’s brain as he performed certain tasks. First, MX looked at faces of famous people and named them. The scientists found that certain regions of his brain became active, the same ones that become active in other people who look at faces.


Then the scientists showed names to MX and asked him to picture their faces. In normal brains, some of those face-recognition regions again become active. In MX’s brain, none of them did.


Paradoxically, though, MX could answer questions that would seem to require a working mind’s eye. He could tell the scientists the color of Tony Blair’s eyes, for example, and name the letters of the alphabet that have low-hanging tails, like g and j. These tests suggested his brain used some alternate strategy to solve visual problems.


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De novo mutations in PLXND1 and REV3L cause Mobius syndrome (facial paralysis)

De novo mutations in PLXND1 and REV3L cause Mobius syndrome (facial paralysis) | Amazing Science | Scoop.it

study published online today in Nature Communications supports the notion that a rare neurological facial paralysis condition called Möbius syndrome can stem from new genetic glitches not found in parents of individuals with the disease.


An international team led by investigators in the Netherlands did exome sequencing on two children with Möbius syndrome and their unaffected parents, along with candidate gene sequencing in half a dozen isolated individuals with the condition. After narrowing in on a handful of genes with suspicious de novo mutations, the group did screening in another 103 affected individuals to find still more de novo mutations in two genes coding for components of hindbrain development pathways: PLXND1 and REV3L.


In follow-up experiments in a mouse model system, meanwhile, the researchers found that interfering with the corresponding mouse genes could produce symptoms resembling those found in individuals with Möbius syndrome. That not only suggests the newfound genetic glitches could be causative, they argued, but underlines the potential of finding such alterations through family sequencing-based approaches.


"Taken together, the present data establish de novo mutations as a cause for [Möbius syndrome]," the study's authors wrote, "providing a rationale for exome sequencing in patient-parent trios to identify de novo mutations in other genes underlying [Möbius syndrome]."


In the past, the researchers noted that there has been some debate about the relative importance of genetic and environmental factors in producing Möbius syndrome. The congenital condition has been linked to oxygen deprivation in the hindbrain due to exposure to certain drugs during pregnancy, for example, though an inherited syndrome resembling Möbius syndrome can also result from recessive mutations affecting the HOXB1 gene.


To dig into potential genetic causes further, the study's authors started by using the Life Technologies SOLiD 4 system to sequence protein-coding genes that had been captured with the Agilent SureSelect Human All Exon v2 50 Mb kit from two individuals with Möbius syndrome and their parents. They also did Sanger sequencing on several candidate genes in another six individuals with isolated Möbius syndrome.


Within one of the trios, the team tracked down de novo mutations in the chromosome 3 gene PLXND1, while three of the unrelated individuals had de novo mutations in the PLXND1, REV3L, and CCDC160 genes.

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Autism and prodigy share a common genetic link

Autism and prodigy share a common genetic link | Amazing Science | Scoop.it

Researchers have uncovered the first evidence of a genetic link between prodigy and autism. The scientists found that child prodigies in their sample share some of the same genetic variations with people who have autism. These shared genetic markers occur on chromosome, according to the researchers from The Ohio State University and Nationwide Children’s Hospital in Columbus.


The findings confirm a hypothesis made by Joanne Ruthsatz, co-author of the study and assistant professor of psychology at Ohio State’s Mansfield campus. In a previous study, Ruthsatz and a colleague had found that half of the prodigies in their sample had a family member or a first- or second-degree relative with an autism diagnosis.


“Based on my earlier work, I believed there had to be a genetic connection between prodigy and autism and this new research provides the first evidence to confirm that,” Ruthsatz said.


The new study appears online in the journal Human Heredity.


These findings are the first step toward answering the big question, Ruthsatz said. “We now know what connects prodigy with autism. What we want to know is what distinguishes them. We have a strong suspicion that there’s a genetic component to that, as well, and that’s the focus of our future work,” she said.


The Human Heredity study involved five child prodigies and their families that Ruthsatz has been studying, some for many years. Each of the prodigies had received national or international recognition for a specific skill, such as math or music. All took tests to confirm their exceptional skills.


The researchers took saliva samples from the prodigies, and from between four and 14 of each prodigy’s family members. Each prodigy had between one and five family members in the study who had received a diagnosis on the autism spectrum.

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FDA permits marketing of first direct-to-consumer genetic carrier test for Bloom syndrome

FDA permits marketing of first direct-to-consumer genetic carrier test for Bloom syndrome | Amazing Science | Scoop.it

The U.S. Food and Drug Administration today authorized for marketing 23andMe’s Bloom Syndrome carrier test, a direct-to-consumer (DTC) genetic test to determine whether a healthy person has a variant in a gene that could lead to their offspring inheriting the serious disorder.


Along with this authorization, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market.


“The FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information. Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “These tests have the potential to provide people with information about possible mutations in their genes that could be passed on to their children.”


In general, carrier testing is a type of genetic testing performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children. A carrier for a genetic disorder has inherited one normal and one abnormal allele for a gene associated with the disorder. A child must inherit two abnormal alleles, one copy from each parent, in order for symptoms to appear.

No test is perfect. Given the probability of erroneous results and the rarity of these mutations, professional societies typically recommend that only prospective parents with a family history of a genetic disorder undergo carrier screening. For example, when a gene mutation is expected to be very rare, a positive result for the mutation may have a high probability of being wrong.


Like other home-use tests for medical purposes, the FDA requires the results to be conveyed in a way that consumers can understand and use. This is the same approach the FDA has taken with other over-the-counter consumer products such as pregnancy, cholesterol and HIV tests for home use


While the FDA is not limiting who should or should not use these tests, it is requiring that the company explain to the consumer in the product labeling what the results might mean for prospective parents interested in seeing if they carry a genetic disorder.  


If sold over the counter, the FDA is also requiring 23andMe to provide information to consumers about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counseling. 23andMe performed two separate studies to demonstrate that their test is accurate in detecting Bloom syndrome carrier status. One study conducted at two laboratories tested a total of 123 samples, including samples from known carriers of the disease. An additional study evaluated 105 samples at two additional laboratories. Both studies showed equivalent results in detecting carrier status of Bloom syndrome when the same samples were tested.


The company also conducted a usability study with 295 people not familiar with the 23andMe saliva collection device to demonstrate consumers could understand the test instructions and collect an adequate saliva sample.


Finally, the company conducted a user study of 302 randomly recruited participants representing the U.S. general population in age, gender, race and education level to show the test instructions and results were easy to follow and understand.

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Human ancestors may have begun evolving the knack for consuming alcohol about 10 million years ago

Human ancestors may have begun evolving the knack for consuming alcohol about 10 million years ago | Amazing Science | Scoop.it

The ability to break down alcohol likely helped human ancestorsmake the most out of rotting, fermented fruit that fell onto the forest floor, the researchers said. Therefore, knowing when this ability developed could help researchers figure out when these human ancestors began moving to life on the ground, as opposed to mostly in trees, as earlier human ancestors had lived. "A lot of aspects about the modern human condition — everything from back pain to ingesting too much salt, sugar and fat — goes back to our evolutionary history," said lead study author Matthew Carrigan, a paleogeneticist at Santa Fe College in Gainesville, Florida. "We wanted to understand more about the modern human condition with regards to ethanol," he said, referring to the kind of alcohol found in rotting fruit and that's also used in liquor and fuel.


To learn more about how human ancestors evolved the ability to break down alcohol, scientists focused on the genes that code for a group of digestive enzymes called the ADH4 family. ADH4 enzymes are found in the stomach, throat and tongue of primates, and are the first alcohol-metabolizing enzymes to encounter ethanol after it is imbibed. The researchers investigated the ADH4 genes from 28 different mammals, including 17 primates. They collected the sequences of these genes from either genetic databanks or well-preserved tissue samples.


The scientists looked at the family trees of these 28 species, to investigate how closely related they were and find out when their ancestors diverged. In total, they explored nearly 70 million years of primate evolution. The scientists then used this knowledge to investigate how the ADH4 genes evolved over time and what the ADH4 genes of their ancestors might have been like.


Then, Carrigan and his colleagues took the genes for ADH4 from these 28 species, as well as the ancestral genes they modeled, and plugged them into bacteria, which read the genes and manufactured the ADH4 enzymes. Next, they tested how well those enzymes broke down ethanol and other alcohols. This method of using bacteria to read ancestral genes is "a new way to observe changes that happened a long time ago that didn't fossilize into bones," Carrigan said.


The results suggested there was a single genetic mutation 10 million years ago that endowed human ancestors with an enhanced ability to break down ethanol. "I remember seeing this huge difference in effects with this mutation and being really surprised," Carrigan said. The scientists noted that the timing of this mutation coincided with a shift to a terrestrial lifestyle. The ability to consume ethanol may have helped human ancestors dine on rotting, fermenting fruit that fell on the forest floor when other food was scarce.

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Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs

Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs | Amazing Science | Scoop.it
On average, every person carries mutations that inactivate at least one copy of 200 or so genes and both copies of around 20 genes. However, knockout mutations in any particular gene are rare, so very large populations are needed to study their effects. These ‘loss of function’ mutations have long been implicated in certain debilitating diseases, such as cystic fibrosis. Most, however, seem to be harmless — and some are even beneficial to the persons carrying them. “These are people we’re not going to find in a clinic, but they’re still really informative in biology,” says MacArthur.

His group and others had been focusing on genome data, but they are now also starting to mine patient-health records to determine the — sometimes subtle — effects of the mutations. In a study of more than 36,000 Finnish people, published in July (E. T. Lim et al. PLoS Genet. 10, e1004494; 2014), MacArthur and his team discovered that people lacking a gene called LPA might be protected from heart disease, and that another knockout mutation, carried in one copy of a gene by up to 2.4% of Finns, may cause fetuses to miscarry if it is present in both copies.

Bing Yu of the University of Texas Health Science Center in Houston told the meeting how he and his collaborators had compared knockout mutations found in more than 1,300 people with measurements of around 300 molecules in their blood. The team found that mutations in one gene, called SLCO1B1, were linked to high levels of fatty acids, a known risk factor for heart failure. And a team from the Wellcome Trust Sanger Institute in Hinxton, UK, reported that 43 genes whose inactivation is lethal to mice were found to be inactivated in humans who are alive and apparently well.


The poster child for human-knockout efforts is a new class of drugs that block a gene known as PCSK9 (see Nature 496, 152–155; 2013). The gene was discovered in French families with extremely high cholesterol levels in the early 2000s. But researchers soon found that people with rare mutations that inactivate one copy of PCSK9 have low cholesterol and rarely develop heart disease. The first PCSK9-blocking drugs should hit pharmacies next year, with manufacturers jostling for a share of a market that could reach US$25 billion in five years.


“I think there are hundreds more stories like PCSK9 out there, maybe even thousands,” in which a drug can mimic an advantageous loss-of-function mutation, says Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California. Mark Gerstein, a bio­informatician at Yale University in New Haven, Connecticut, predicts that human knockouts will be especially useful for identifying drugs that treat diseases of ageing. “You could imagine there’s a gene that is beneficial to you as a 25-year-old, but the thing is not doing a good job for you when you’re 75.”

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Schizophrenia is not a single disease but rather consists of eight different genetically distinct classes

Schizophrenia is not a single disease but rather consists of eight different genetically distinct classes | Amazing Science | Scoop.it

New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.


The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry. About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition.


Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.


“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.” 

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness. 

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Single gene (Lhx1) found to control jet lag

Single gene (Lhx1) found to control jet lag | Amazing Science | Scoop.it

The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travelers adjust to time differences more quickly. The results, published in eLife, can point to treatment strategies for sleep problems caused by a variety of disorders.


“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”


Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.


More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.


In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.


“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.

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Friends Are the Family You Choose: Genome-Wide Analysis Reveals Genetic Similarities Among Friends

Friends Are the Family You Choose: Genome-Wide Analysis Reveals Genetic Similarities Among Friends | Amazing Science | Scoop.it

If you consider your friends family, you may be on to something. A study from the University of California, San Diego, and Yale University finds that friends who are not biologically related still resemble each other genetically.


Published in the Proceedings of the National Academy of Sciences, the study is coauthored by James Fowler, professor of medical genetics and political science at UC San Diego, and Nicholas Christakis, professor of sociology, evolutionary biology, and medicine at Yale.


“Looking across the whole genome,” Fowler said, “we find that, on average, we are genetically similar to our friends. We have more DNA in common with the people we pick as friends than we do with strangers in the same population.”


The study is a genome-wide analysis of nearly 1.5 million markers of gene variation, and relies on data from the Framingham Heart Study. The Framingham dataset is the largest the authors are aware of that contains both that level of genetic detail and information on who is friends with whom.


The researchers focused on 1,932 unique subjects and compared pairs of unrelated friends against pairs of unrelated strangers. The same people, who were neither kin nor spouses, were used in both types of samples. The only thing that differed between them was their social relationship.


The findings are not, the researchers say, an artifact of people’s tendency to befriend those of similar ethnic backgrounds. The Framingham data is dominated by people of European extraction. While this is a drawback for some research, it may be advantageous to the study here: because all the subjects, friends and not, were drawn from the same population. The researchers also controlled for ancestry, they say, by using the most conservative techniques currently available. The observed genetic go beyond what you would expect to find among people of shared heritage – these results are “net of ancestry,” Fowler said.

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Genetic cause behind hemifacial microsomia found: Transcription factor OTX2 is to blame

Genetic cause behind hemifacial microsomia found: Transcription factor OTX2 is to blame | Amazing Science | Scoop.it

Whitehead Institute scientists have identified a genetic cause of a facial disorder known as hemifacial microsomia (HFM). The researchers find that duplication of the geneOTX2 induces HFM, the second-most common facial anomaly after cleft lip and palate. HFM affects approximately one in 3,500 births. While some cases appear to run in families, no gene had been found to be causative. That is until Whitehead Fellow Yaniv Erlich and his lab set out to do just that. Their work is described in this week’s issue of the journal PLOS ONE.


Patients with HFM tend to have asymmetrical faces—typically with one side of the upper and lower jaws smaller than the opposite side—a smaller or malformed ear on the affected side, and, in some cases, neurological or developmental abnormalities. Thought to be brought on by circulation difficulties during embryonic development, HFM is also thought to be sporadic—meaning that it occurs spontaneously rather than through inheritance. However, one family in northern Israel has more than its share of the anomaly.


To identify the origin of this family’s disorder, Erlich and lab technician Dina Zielinski began studying the genomes of a five-year-old female member of the family, along with those of her mother, grandmother, and male cousin, who all exhibited traits of HFM. Later, the genetic information from the grandmother’s Russian cousin, who resides in the Philadelphia area, was recruited to the study.


“What’s unique here is that this is the largest family with this disorder described in the literature,” says Erlich. “Most of the time, you see one person affected, or perhaps two people—a parent and a child. Such a large family increases the power of the genetic study and clearly signals that there is a genetic component to a disease.”


Within this large piece of DNA, Zielinski identified eight candidate genes that could cause the type of HFM running in this family. She then used two algorithms to compare the molecular signatures of these eight genes to other genes known to be responsible for various facial malformations with features similar to HFM. After this analysis, the gene OTX2 that codes for a transcription factor rose above the seven other candidates.


These results are supported by what is known of OTX2’s function. Previous data indicates that the gene codes for a protein that is expressed in the heads and pharyngeal arches of mouse embryos in developmental stages corresponding to the periods when HFM abnormalities are thought to arise in humans.


Although this is a tantalizing hint as to OTX2’s activity during development, Zielinski cautions that little is known about its overall role, in part because it serves as a transcription factor that regulates other genes.


OTX2’s activity is very complicated,” says Zielinski, who is first author of the PLOS ONE paper. “Development is dependent on tight control of these transcription factors that turn other genes on and off. The feedback between OTX2 and other transcription factors is complex but we know thatOTX2 plays a critical role in craniofacial patterning.”

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The milk revolution: A single genetic mutation first let ancient Europeans drink milk

The milk revolution: A single genetic mutation first let ancient Europeans drink milk | Amazing Science | Scoop.it

When a single genetic mutation first let ancient Europeans drink milk, it set the stage for a continental upheaval. During the most recent ice age, milk was essentially a toxin to adults because — unlike children — they could not produce the lactase enzyme required to break down lactose, the main sugar in milk. But as farming started to replace hunting and gathering in the Middle East around 11,000 years ago, cattle herders learned how to reduce lactose in dairy products to tolerable levels by fermenting milk to make cheese or yogurt. Several thousand years later, a genetic mutation spread through Europe that gave people the ability to produce lactase — and drink milk — throughout their lives.


Young children almost universally produce lactase and can digest the lactose in their mother's milk. But as they mature, most switch off the lactase gene. Only 35% of the human population can digest lactose beyond the age of about seven or eight (2). “If you're lactose intolerant and you drink half a pint of milk, you're going to be really ill.


Most people who retain the ability to digest milk can trace their ancestry to Europe, where the trait seems to be linked to a single nucleotide in which the DNA base cytosine changed to thymine in a genomic region not far from the lactase gene. There are other pockets of lactase persistence in West Africa (see Nature 444994996; 2006), the Middle East and south Asia that seem to be linked to separate mutations3 (so called 'Lactase hotspots').


The single-nucleotide switch in Europe happened relatively recently. Thomas and his colleagues estimated the timing by looking at genetic variations in modern populations and running computer simulations of how the related genetic mutation might have spread through ancient populations4. They proposed that the trait of lactase persistence, dubbed the LP allele, emerged about 7,500 years ago in the broad, fertile plains of Hungary.


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Woher kommt die Fähigkeit zur Verdauung von Laktase? Neue genetische Studien bringen hier Licht ins Dunkel.

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Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance

Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance | Amazing Science | Scoop.it

Sustained or repeated exposure to sedating drugs such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state.


Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study.


A research team now used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. They surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. The identified a network of genes that are essential for the development of tolerance to sedation by alcohol.

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